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The synthesis and evaluation of 8-benzyloxycaffeine analogues as inhibitors of monoamine oxidase B / Belinda Strydom

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dc.contributor.author Strydom, Belinda
dc.date.accessioned 2012-01-03T10:53:37Z
dc.date.available 2012-01-03T10:53:37Z
dc.date.issued 2009
dc.identifier.uri http://hdl.handle.net/10394/4986
dc.description Thesis (M.Sc. (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2010.
dc.description.abstract Monoamine oxidase, especially monoamine oxidase 8 (MAO-B), plays a major role in the therapy of Parkinson's disease (PO). MAO-8 is the main enzyme responsible for the catabolism of dopamine in the substantia nigra of the brain. Inhibition of MAO-8 may thus conserve dopamine in the brain and provide symptomatic relief to PO patients. MAO inhibitors are currently being studied as a treatment strategy for neurodegenerative diseases such as PD. In addition to symptomatic relief, MAO inhibitors are also thought to have neuroprotective properties and may slow the neurodegenerative process and thus the progress of the disease. The most common MAO-B inhibitor used for the treatment of PO is selegiline [(R)-deprenyl], an irreversible inhibitor. Unfortunately, selegiline has psycotoxic and cardiovascular adverse effects due to amphetamine metabolites formed during its oxidation. This justifies the need for the development of novel, safe and reversible MAO-8 inhibitors for the treatment of PD. Among recently discovered reversible inhibitors of MAO-B are safinamide and (E)-8-(3-chlorostyryl) caffeine (CSC). CSC consists of a caffeine ring with a styryl side chain at C-8 of the caffeine ring. 80th of these moieties are critical to CSC's MAO-8 inhibition activity since CSC exhibits a dual binding mode with the caffeine ring located in the substrate cavity of the enzyme while the styryl side chain extends into the entrance cavity. Safinamide also exhibits this dual binding mode, but in this case it is the benzyloxy side chain which extends into the entrance cavity of the enzyme. In this study we examined the effect of benzyloxy substitution at C-8 of caffeine on MAO-8 inhibition activity by synthesizing a series of 8-benzyloxycaffeine analogues and by evaluating them' as inhibitors of MAO. The target compounds were synthesized by condensing 8-chlorocaffeine with the appropriate benzylalcohol at high temperatures in the presence of metallic sodium. The inhibitory activity of the compounds toward baboon liver MAO-B and recombinant human MAO-A and -B were measured and expressed as ICso values. The ICso values obtained for human MAO-B compared very well to that of mitochondrial baboon liver MAO-B, which indicates that the active sites and inhibitor specificities of these two enzymes are very similar. Baboon liver MAO-B was most potently inhibited by 8-(3trifluoromethylbenzyloxy)caffeine with an ICso value of 0.112 ± 0.016 IJM. Human MAO-B on the other hand was most potently inhibited by 8-(3-bromobenzyloxy)caffeine with an ICso value of 0.068 ± 0.003 IJM. These inhibitors are more potent than CSC, the lead compound for this study, which has an ICso value of 0.146 ± 0.001 IJM for MAO-B. From these results it can be concluded that substitution of caffeine at C-8 with a benzyloxy side chain is at least as effective as substitution with a styryl side chain for enhancing MAO-B inhibitory activity. 8-Benzyloxycaffeine and its analogues proved to be inhibitors of human MAO-A as well, although less potent compared to MAO-B. The most potent inhibitor was 8-(3methylbenzyloxy)caffeine with an ICso value of 0.397 ± 0.013 µM. It was determined that the target compounds bind reversibly to all three enzymes and that the mode of inhibition is competitive. A Hansch-type structure-activity relationship (SAR) study showed that MAO-B inhibition activities correlated negatively with the Hansch lipophilicity constant (rr) and the Hammett constant (ŏ) of the substituent at C-3 of the benzyloxy ring. This means that more hydrophobic and electron withdrawing substituents will result in better inhibitors of human as well as baboon liver MAO-B. Docking studies further revealed that the 8-benzyloxycaffeine analogues traverse both cavities of MAO-B with the caffeine ring oriented towards the FAD-cofactor while the benzyloxy side chain protrudes into the entrance cavity. The 8-benzyloxycaffeine analogues oriented itself similarly within the MAO-A cavity with the bezyloxy side chain rotated to avoid steric interaction with the Phe 208 residue. The observation that 8-benzyloxycaffeine and its analogues inhibit both MAO-B and MAO-A make these compounds ideal drug candidates since both enzymes are targets for the treatment of PD.
dc.language.iso en en_US
dc.publisher North-West University
dc.title The synthesis and evaluation of 8-benzyloxycaffeine analogues as inhibitors of monoamine oxidase B / Belinda Strydom en_US
dc.type Thesis en_US
dc.description.thesistype Masters en_US


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    This collection contains the original digitized versions of research conducted at the North-West University (Potchefstroom Campus)

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